Role of DPP4 in Kidney Inflammation and Injury

项目摘要/摘要 慢性肾脏疾病(CKD)的发病率正在增加，原因是 要么肥胖(33%)，要么糖尿病(9%)，或者两者兼而有之。在相当大比例的肥胖糖尿病受试者中，慢性肾脏病可能 进展到终末期肾病(ESRD)和透析比非肥胖糖尿病受试者更快。终末期肾病的护理 患者(占联邦医疗保险人口的1%)以不成比例的方式消费医疗保险美元(7%)。因此， 防止CKD进展为终末期肾病是至关重要的。目前，护理的标准是使用 阻断/抑制肾素-血管紧张素系统激活的药物。然而，这些药物并不是 足以阻止许多受试者进展为ESRD，需要新的治疗剂。DPP4抑制剂 被方便地放置在糖尿病和CKD的交界处，因为最近的数据显示 慢性肾脏病糖尿病患者的蛋白尿(SAVOR-TIMI试验和动物模型)。尼斯塔拉博士和其他人 研究表明，DPP4抑制剂可能具有独立于血压或血糖的肾脏特异性效应 进步。然而，DPP4抑制剂介导的肾脏益处的机制相对较少。 未知。如果要使用DPP4抑制剂来防止肾脏疾病的进展，其生物学功能 DPP4在肾脏中的作用需要更好的了解。数据支持DPP4可能调节钠的观点 肾脏近端小管的吸收和白蛋白/低聚肽内吞作用。此外，DPP4是一种 T淋巴细胞共刺激分子，激活单个核细胞(包括巨噬细胞和抗原 提呈细胞[APC])，并可能基于肥胖者和血浆中脂肪库的发现而介导炎症 从糖尿病患者那里。肾小管间质炎症和纤维化在肾小球肾炎的发生发展中起重要作用 CKD在肥胖和糖尿病的背景下，重要的是，Nistala博士发现DPP4的活性在 肥胖/糖尿病小鼠肾脏和近端小管的表达水平较高。因此，这个项目 重点研究了DPP4在近曲小管和肾脏免疫系统中的作用 肥胖/糖尿病。这些实验旨在解决肥胖的核心假设-- 诱导的近端小管DPP4激活激发促炎免疫反应导致 肾小管间质纤维化与肾脏疾病进展。为了解决这一假设，DPP4将是 在有或没有DPP4缺乏的小鼠中，通过高蔗糖/高脂肪(西方饮食)喂养而激活。在目标1中， 我们将研究西方饮食在近曲小管DPP4激活和肾小管功能障碍中的作用。 近端小管特异缺失DPP4。在目标2，近端小管DPP4在肾脏免疫系统中的作用 将检查激活情况。在目标3中，近端小管DPP4诱导的免疫系统激活在 将对肾小管间质纤维化和肾脏疾病进展进行研究。预计由此产生的结果是 该项目将对肥胖/糖尿病的肾脏损伤和炎症机制产生独特的见解 将这些发现转化为有意义的治疗方法的最终目标。

Project Summary/Abstract The incidence of chronic kidney disease (CKD) is increasing due to the ever-expanding number of people who are either obese (33%) or diabetic (9%) or both. In a significant proportion of obese-diabetic subjects, CKD may progress to end stage renal disease (ESRD) and dialysis faster than non-obese diabetic subjects. Care of ESRD patients (1% of Medicare population) consumes Medicare dollars in a disproportional manner (7%). Hence, preventing progression of CKD to ESRD is of paramount importance. Currently, the standard of care is to use medications that block/suppress activation of the renin-angiotensin system. However, these medications are not enough to stop progression to ESRD in many subjects and novel therapeutic agents are needed. DPP4 inhibitors are conveniently placed at the intersection of diabetes and CKD due to recent data showing improvement in proteinuria in diabetic patients with CKD (SAVOR-TIMI trial and animal models). Dr. Nistala and others have shown that DPP4 inhibitors may have kidney specific effects independent of blood pressure or blood sugar improvement. However, the mechanisms of DPP4 inhibitor-mediated benefits in the kidney are relatively unknown. If DPP4 inhibitors are to be used for preventing progression of kidney disease, the biological function of DPP4 in the kidney needs better understanding. Data supports the notion that DPP4 may regulate sodium absorption and albumin/oligomeric peptide endocytosis in proximal tubules of the kidney. In addition, DPP4 is a co-stimulatory molecule for T-lymphocytes, activates mononuclear cells (including macrophages and antigen presenting cells [APCs]) and may mediate inflammation based on findings from fat depots in obese and plasma from diabetes patients. Tubulointerstitial inflammation and fibrosis plays an important role in the progression of CKD in the setting of obesity and diabetes and importantly, Dr. Nistala found that DPP4 activity is increased in the kidney and expression levels are higher in the proximal tubules of obese/diabetic mice. Therefore, this project is focused on examining the role of DPP4 in the proximal tubule and kidney immune system in the setting of obesity/diabetes. The experiments are designed to address the central hypothesis that obesity- induced proximal tubule DPP4 activation incites a pro-inflammatory immune response leading to tubulointerstitial fibrosis and progression of kidney disease. To address this hypothesis, DPP4 will be activated via high sucrose/high fat (Western Diet) feeding in mice with or without DPP4 deficiency. In Aim 1, the role of Western diet in activation of DPP4 in the proximal tubule and tubular dysfunction will be studied by using proximal tubule specific deletion of DPP4. In Aim 2, the role of proximal tubule DPP4 in kidney immune system activation will be examined. In Aim 3, the role of proximal tubule DPP4-induced immune system activation in tubulointerstitial fibrosis and kidney disease progression will be studied. It is anticipated that results from this project will yield unique insights into the mechanisms of kidney injury and inflammation in obesity/diabetes with the ultimate goal of translating these findings into meaningful treatments.